© 1997 American Heart Association, Inc.
Articles |
Homocyst(e)ine and Risk of Cardiovascular Disease in the Multiple Risk Factor Intervention Trial
From the Departments of Epidemiology (R.W.E., L.H.K.) and Biological Sciences (J.D.H.), University of Pittsburgh, Pittsburgh, Penn; the MRFIT Coordinating Center, Division of Biostatistics, University of Minnesota, Minneapolis, Minn (B.J.S.); and the Division of Epidemiology and Clinical Applications, National Heart, Lung, and Blood Institute, Bethesda, Md (J.A.C.).
Correspondence to R.W. Evans, PhD, University of Pittsburgh, Graduate School of Public Health, Department of Epidemiology, 503 Parran Hall, 130 DeSoto St, Pittsburgh, PA 15261. E-mail RWE2{at}vms.cis.pitt.edu.
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Abstract |
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Abstract A nested case-control study was undertaken involving men participating in the Multiple Risk Factor Intervention Trial (MRFIT). Serum samples from 712 men, stored for up to 20 years, were analyzed for homocyst(e)ine. Cases involved nonfatal myocardial infarctions (MIs), identified through the active phase of the study, which ended on February 28, 1982, and deaths due to coronary heart disease (CHD), monitored through 1990. The nonfatal MIs occurred within 7 years of sample collection, whereas the majority of CHD deaths occurred more than 11 years after sample collection. Mean homocyst(e)ine concentrations were in the expected range and did not differ significantly between case patients and control subjects: MI cases, 12.6 µmol/L; MI controls, 13.1 µmol/L; CHD death cases, 12.8 µmol/L; and CHD controls, 12.7 µmol/L. Odds ratios versus quartile 1 for CHD deaths and MIs combined were as follows: quartile 2, 1.03; quartile 3, 0.84; and quartile 4, 0.92. Thus, in this prospective study, no association of homocyst(e)ine concentration with heart disease was detected. Homocyst(e)ine levels were weakly associated with the acute-phase protein (C-reactive protein). These results are discussed with respect to the suggestion that homocyst(e)ine is an independent risk factor for heart disease.
Key Words: homocyst(e)ine • cardiovascular disease • MRFIT • prospective
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Introduction |
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An elevated serum level of the amino acid homocyst(e)ine is a possible risk factor for cardiovascular disease.1 Children with homocystinuria have premature vascular disease and increased risks of both stroke and MI.2 Genetic defects of several enzymes that result in very high homocyst(e)ine levels are associated with early onset of vascular disease.3 Several B vitamins (B12, B6, and folic acid) are involved in homocyst(e)ine metabolism,4 and serum folate levels are inversely related to blood homocyst(e)ine concentrations. Reduced dietary consumption of these vitamins has been linked to higher homocyst(e)ine values,4 5 whereas supplementation with vitamins, especially folic acid, has resulted in diminished homocyst(e)ine levels.1 The blood levels of homocyst(e)ine among individuals with decreased vitamin intake are, however, much lower than they are for individuals with genetic disorders of the major enzymes involved in homocyst(e)ine metabolism.6
Homocyst(e)ine is derived metabolically from methionine, an amino acid found at high concentrations in animal proteins. Increasing intake of methionine (by methionine loading) will acutely raise the homocyst(e)ine level of blood.3 There is, however, no conclusive evidence that increasing methionine or animal protein in the diet results in chronically higher concentrations of homocyst(e)ine in the blood of individuals with adequate intake of vitamins B6, B12, and folic acid. Several studies have documented that low dietary or serum folate levels may be related to the risk of vascular disease, both incident CHD and stroke.7 8 9
Suggested mechanisms by which homocyst(e)ine may increase the risk of vascular disease1 include a direct effect on the vascular endothelium10 11 and a role in enhancing the risk of thrombosis.12
There have been numerous retrospective case-control studies of the relationship between homocyst(e)ine levels and CHD, peripheral vascular disease, and stroke. These studies were recently reviewed by Boushey et al.13 Based on the results of 16 studies, a 5-µmol/L increase in homocyst(e)ine was estimated to result in a 1.6-fold OR for CHD.
There have been few prospective studies of the relationship between homocyst(e)ine and risk of cardiovascular disease.14 Investigators in a Finnish study compared 7424 men and women 40 to 69 years old over a 9-year period and reported no significant difference in homocyst(e)ine level between the 191 patients with MI and the control subjects.15 In the Zutphen study in Holland, investigators followed 868 men aged 64 to 84 years for 5 years and noted an increased risk of death due to CHD (52 cases) associated with homocyst(e)ine concentrations only during the first 1.5 years of follow-up.16 In the Tromso study,17 in which 21 826 men ages 12 to 61 years were evaluated, there were 123 cases of MI. There was an increased risk of about 40% for incident MI associated with a 1-SD, 4-µmol/L increase in homocyst(e)ine levels. Investigators in the Physicians' Health Study initially reported in 1992 that high homocyst(e)ine levels, in the upper 5% of the distribution, were associated with a 3.1-fold (1.3 to 8.8) relative risk of CHD.18 Investigators in a longer 10- to 12-year follow-up of the same study (333 MI case patients and control subjects) reported a relative risk of 1.7 that was not significant.19 Another report from the Physicians' Health Study, but involving a five-year follow up of ischemic stroke events (109 cases), noted an OR of 1.4 that was not significant.20 The investigators for the British Regional Heart Study followed 5661 men from 1978-1980 to 1991 (12.8 years) and noted 141 cases of stroke.21 The risk of stroke was directly related to the blood homocyst(e)ine concentrations, with relative risks in quartiles 2, 3, and 4 of 1.3, 1.9, and 2.8, respectively (P=.005). Petri and colleagues22 evaluated the association between homocyst(e)ine levels and the risk of stroke and thrombosis in 337 patients with systemic lupus erythematosus. The homocyst(e)ine concentrations were an independent risk factor for both stroke (OR=2.44) and thrombotic events (OR=3.49).
Therefore, to date, the prospective studies, mostly nested case-control studies, do not demonstrate a consistent association between blood homocyst(e)ine levels and risk of CHD or stroke. We evaluated the relationship between serum homocyst(e)ine levels and risk of MI and CHD death in MRFIT using a large number of stored serum samples in a nested case-control study.
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Methods |
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Design and End Points
In this study we used a nested case-control design and stored serum samples from MRFIT to evaluate the relationship between homocyst(e)ine levels and risk of CHD and MI among white men aged 35 to 57 years at entry to the study.23
The methodology of MRFIT has previously been described in detail.24 The trial enrolled 12 866 men aged 35 to 57 years, randomized in 22 centers, between December 1973 and February 1976.24 The men were at a moderately high risk for CHD at entry based on a combination of their total serum cholesterol level, diastolic blood pressure, and number of cigarettes smoked at the time of the first screening examination. Nevertheless, because of exclusion criteria involving morbidity, the men were generally healthy, tempering the risk of CHD. The number of deaths due to CHD at the end of the trial was less than expected. The cumulative CHD mortality rate was only 1.8% in the "special intervention" group and 1.9% in the "usual care" group over 6 years.24 The men had three clinic visits before randomization, and during their second visit a serum sample was collected. These samples were used in the current study. Serum samples were stored at -50 to -70°C in freezers equipped with 24-hour alarms. The serum samples were analyzed for homocyst(e)ine in the Nutrition Laboratory at the Graduate School of Public Health at the University of Pittsburgh.
The active phase of intervention and follow-up was completed on February 28, 1982. Monitoring of post-trial mortality, using the National Death Index and death certificates obtained from state health departments, continued through December 31, 1990.23 Nonfatal MIs were identified only during the active phase of the study through February 28, 1982 (the methods of ascertaining nonfatal MIs are described elsewhere).24 There were 1161 instances of nonfatal MI and 789 CHD deaths noted during the trial; of these, 8.0% and 18.6%, respectively, were used in the current study. Many of the serum samples from participants who died of CHD in the early years of follow-up had already been depleted during previous nested case-control studies. The majority of samples for this study, therefore, are from the later follow-up period, generally from 11 to 17 years after the serum had been obtained at the second screening.23 Ninety-three nonfatal MI cases (all occurring within 7 years of sample collection) and 147 CHD deaths (92.5% occurring 11 or more years after sample collection) were available for the measurement of homocyst(e)ine out of a total of 100 nonfatal MIs and 150 CHD deaths included in a previous nested case-control study using the same serum samples. Details of this study, which involved CRP, are given in Kuller et al.23
Control subjects (186 for MIs and 286 for CHD deaths) were matched to the case patients by age (±5 years), smoking status, clinic, race, and study group (special intervention or usual care). Two control subjects were selected for each case patient. Among the 472 control subjects selected for the study, 49 subsequently died (10.4%), 17 among those matched to MI case patients and 32 among those matched to CHD death case patients. Thirteen of these 49 deaths were due to lung cancer, and 9 were due to other cardiovascular diseases. Among the MI cases, 15 subsequently died, 6 of CHD and 3 of other cardiovascular diseases. Five samples with very high levels of homocyst(e)ine (63.5 to 80.4 µmol/L) (3 control subjects and 2 case patients) were omitted from the logistic regression analysis.
Laboratory Methods
Total serum homocyst(e)ine was analyzed according to the
procedure of Jacobsen et al.25 Each case sample and its
two matched control samples were assayed together as a triad, and the
laboratory was blinded to the case-control status of the participants.
Samples (100 µL) were mixed with 10 µL of water and 5 µL of
n-amyl alcohol. Subsequently, 35 µL of 1.43 mol
NaBH4 in 0.1 mol NaOH was added; after vortexing, 35 µL
of 1-N HCl was introduced. After mixing, the homocyst(e)ine was
incubated at 42°C for 12 minutes with 50 µL of 10 mmol
monobromobinane (thiolyte) in 4 mmol sodium EDTA (pH 7.0). The
samples were cooled, then mixed with 50 µL of 1.5-mol perchloric
acid. The samples were left at room temperature for 10 minutes, then
microfuged for 10 minutes. The supernatants were removed, mixed with 25
µL of 2-mol Tris, and microfuged for 1 minute. The supernatants were
aspirated before HPLC. Aliquots (10 µL) were separated on a
4.6-mmx25-cm octyl ultrasphere (5-µm particles) column fitted with a
guard column (4.6x30 mm, ODS-GU, 5 µm). Eluent A was
water/methanol/acetic acid (94.75:5.00:0.25 by vol) titrated to
pH 3.40 with 5 mM NaOH. Eluent B was 100% methanol. Total flow rate
was 2 mL/min, and the solution gradient involved minor modifications of
the Jacobsen et al25 method: 0 to 1 minute, 0% B; 1 to 3
minutes, 0% to 10% B; 3 to 9 minutes, 10% to 15% B; 9 to 10
minutes, 15% to 95% B; 10 to 11 minutes, 95% B; 11 to 13 minutes,
95% to 0% B; and 13 to 18 minutes, 0% B. The homocyst(e)ine
derivative was detected fluorometrically with excitation at 390 nm and
emission at >418 nm with a cutoff filter. The HPLC consisted of an
automatic injector, two pumps, a fluorescence detector, a
controller, and an integrator. A calibration curve was generated for
each set of samples and consisted of duplicates of a control pool plus
control pools fortified with 0.5, 1, 2, and 3.33 nmol of
homocyst(e)ine. The between-run coefficient of variation, determined on
a pooled serum sample, was 13.0% based on individual analyses
and 10.1% based on the means of duplicates. Samples were measured in
duplicate. Because this procedure involved a reducing step, the method
did not distinguish between homocysteine and its oxidized analogues.
Therefore, the measured moiety is referred to as
homocyst(e)ine.26
Statistical Methods
Univariate and multivariate ORs for
quartiles of homocyst(e)ine and risks of MI and CHD death were
calculated using logistic regression analysis. Analyses
were conducted separately for smokers and nonsmokers for each end point
(nonfatal MI through February 28, 1982 [the end of the trial]; CHD
death through December 31, 1990; and nonfatal MI and CHD death through
the end of the trial). Reported results are for the combined end point
of nonfatal MI and CHD death.
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Results |
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The baseline characteristics of the case patients and control subjects included in the nested case-control studies were previously published.23 The mean ages of the CHD death case patient, MI case patients, and control subjects were 47, 46, and 46 years, respectively. Mean systolic blood pressure was 134 mm Hg for the MI cases, 136 mm Hg for the CHD death cases, and 135 mm Hg for the control subjects. The mean diastolic blood pressure was approximately 90 mm Hg for all CHD death cases, MI cases, and control subjects, and body mass index was approximately 28 kg/m2 for all case patients and control subjects. Serum cholesterol levels were significantly higher for case patients (CHD death, 258 mg/dL; and MI, 260 mg/dL) than for control subjects (247 mg/dL). Similarly, LDL cholesterol was 171 mg/dL at baseline for the CHD death case patients, 166 mg/dL for the MI case patients, and 156 mg/dL for the control subjects. HDL cholesterol was 42 mg/dL for the control subjects and approximately 39 mg/dL for the MI and CHD death case patients. Mean alcohol intake averaged about 10 to 12 drinks per week and did not differ between the case patients and control subjects.
The distribution of risk factors among both smokers and nonsmokers and
within each of the three groups (CHD death, MI, and control) did not
differ by quartile of homocyst(e)ine level (not shown). Table 1
provides the distribution of risk
factors for smokers and nonsmokers (case patients and control subjects
combined). The mean and median blood homocyst(e)ine concentrations were
similar for each case/control group (Table 2). The distributions of the CHD deaths,
MI cases, and their controls by quartile of homocyst(e)ine was also
similar (Table 3).
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A multiple logistic regression analysis included age, cigarette
smoking, diastolic blood pressure,
triglycerides, LDL cholesterol, and HDL
cholesterol. Compared with quartile 1, quartiles 2, 3, and
4 of homocyst(e)ine were not significantly related to the risks of CHD
death and nonfatal MI (Table 4). Similar
logistic regression analysis restricted to cigarette smokers
also failed to demonstrate any evidence of a significant association
between homocyst(e)ine level and risk of MI or CHD death. Of the five
participants with very high homocyst(e)ine levels who were not included
in these analyses, two were case patients and three were
control subjects.
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Serum was available from only 11 cases of CHD death occurring within the first 5 years of MRFIT. The mean homocyst(e)ine concentration was 15.7 µmol/L, whereas for the remaining 136 cases of CHD death, the homocyst(e)ine level was 12.4 µmol/L, similar to that of the control subjects (12.7 µmol/L).
Cigarette smoking and LDL cholesterol were also significant
risk factors for CHD death and nonfatal MI, whereas HDL
cholesterol was protective (Table 4
). The effects of
triglycerides and diastolic blood pressure
approached significance. In the total MRFIT cohort, LDL
cholesterol, HDL cholesterol, cigarette
smoking, and diastolic blood pressure were significant risk
factors, but triglycerides and body mass index were not
related to CHD mortality in a logistic regression
model.27
There was no correlation between albumin and homocyst(e)ine
levels, but there was a weak direct association between CRP and
homocyst(e)ine levels. For smokers, the homocyst(e)ine level was
approximately 12.6 µmol/L in quartile 1 and 13.9
µmol/L in quartile 4 of CRP
(Figure).
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Discussion |
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The results of this nested case-control study, in which the serum samples were collected before the MIs and CHD deaths occurred, are consistent with those of most other longitudinal studies in failing to demonstrate an increased risk of incident cardiovascular disease with higher serum homocyst(e)ine levels.14 23 The results are clearly different from those of the numerous retrospective case-control studies that demonstrated higher concentrations of homocyst(e)ine among patients with MI and CHD than among control subjects.13 Similarly, case-control studies associate high concentrations of homocyst(e)ine with a higher prevalence of atherosclerosis, as measured by carotid artery wall thickness or stenosis,28 29 and coronary artery disease, as documented by coronary angiography.30 31
There are several possible explanations for the differences between results observed in the longitudinal or prospective studies and those seen in retrospective case-control studies.
First, it is possible that because serum has often been stored for a considerable period of time, the measurement of serum levels of homocyst(e)ine may be compromised. However, published reports indicate that homocyst(e)ine measurements are accurate after extended storage. Alfthan et al,15 in a Finnish study, evaluated sera from 13 subjects that had been stored at -20°C since 1985. The mean level was 9.1 µmol/L in 1985 and 9.3 µmol/L when they were reanalyzed in 1990. Intraindividual coefficients of variation ranged from 6% to 18%, and there was no trend in homocyst(e)ine levels with storage over time. Similarly, Israelsson et al32 evaluated homocyst(e)ine in frozen plasma samples stored for 6 to 16 years. Levels in the stored samples were somewhat lower than they were in the fresh samples, but the fresh and stored values were significantly correlated (r=.58, P<.001).
Levels of homocyst(e)ine reported in this MRFIT study are similar to those noted in other studies. Therefore, it is unlikely that a substantial reduction in homocyst(e)ine concentrations with storage could account for the absence of an effect between quartiles 1 and 4 of homocyst(e)ine levels and risks of CHD death and MI. The storage time was the same for both the case and control samples.
Second, any effect of short-term dietary variation on homocyst(e)ine is also unlikely to account for the failure to find an association between CHD and homocyst(e)ine levels. Guttormsen et al33 reported that after dinner plasma homocyst(e)ine levels exhibited an increase of 13%. All participants in MRFIT fasted before their blood draw, and almost all of them had their blood drawn in the morning. The possibility that a methionine-loading test rather than measurement of fasting homocyst(e)ine would enhance the ability to discriminate risk of CHD has been suggested. However, case-control studies have typically measured only fasting or random homocyst(e)ine levels. Long-term dietary variation, however, remains a possibility: the subjects may have altered their dietary intake, including the use of supplements, which could have lowered homocyst(e)ine levels between the time of sample collection and the cardiovascular event.
Third, it is possible that the associations found in retrospective case-control studies can be attributed to elevations in homocyst(e)ine concentrations that follow an MI or other acute vascular diseases. Higher homocyst(e)ine concentrations among case patients compared to control subjects could therefore be due to the disease (ie, MI or stroke) or to an underlying vascular disease (eg, atherosclerosis) rather than a cause of MI or vascular disease. Prospective studies would tend to diminish this potential bias associated with case-control studies.
Egerton et al34 measured blood homocyst(e)ine values at the time of MI and up to 180 days after the MI. The homocyst(e)ine concentrations were 12.9±0.9 µmol/L (10 patients) on the day of the MI and 15.3±1.1 µmol/L (P=.05) 180 days after the MI. The changes in homocyst(e)ine level between days 1 and 180 were as large as the differences in homocyst(e)ine levels observed in many case-control studies. Similarly, Lindgren et al35 measured homocyst(e)ine values 2 days after a stroke and again after 583 days (460 to 645 days) in 17 patients. The mean homocyst(e)ine level was 11.4 µmol/L in the immediate 2-day samples and 14.5 µmol/L at 583 days. No changes were observed in the homocyst(e)ine concentrations of 20 control subjects over the same time period. Neither of these studies measured homocyst(e)ine levels before the event (MI or stroke) and then over time after the event. It is possible that homocyst(e)ine levels were briefly depressed after the MI or stroke and then returned to pre-MI or -stroke concentrations over the next year. Furthermore, it is possible that these changes reflect alterations in protein intake.
These results have implications for studies that include subjects with preexisting disease in their cohorts. The British Regional Heart Study21 included men with earlier CHD: 37.4% of the subjects who had an incident stroke had a history of coronary artery disease, versus only 5.1% of the control subjects. Men with a history of CHD had much higher homocyst(e)ine levels than those without preexisting CHD (14.3 versus 11.8 µmol/L, respectively). The concentration of homocyst(e)ine for those without preexisting coronary heart disease was similar to that of the control subjects (11.9 versus 11.8 µmol/L, respectively). The association between stroke and homocyst(e)ine was substantially reduced when men with prior CHD were excluded from the analysis, and only the OR for the fourth quartile of homocyst(e)ine remained statistically significant (2.5 [1.1 to 6.1]). Similarly, the Tromso study17 included case patients with a history of angina pectoris (11.5%) and diabetes (6.6%). The Petri et al22 study was restricted to subjects with systemic lupus erythematosus.
Results of two longitudinal nested case-control studies (Zutphen16 and the Physicians' Health Study19 ) suggest that cases occurring within the first few years of the studies had higher homocyst(e)ine levels. In the Physicians' Health Study, the increased risk (overall 1.7) was limited to the first 3.7 years of follow-up (OR=2.8 [0.9 to 8.4]). The risk was only 1.3 (0.5 to 3.1) after 3.75 to 7.0 years of follow-up. Among our MRFIT sample, only 11 deaths were observed within the first 5 years, but the homocyst(e)ine levels of these 11 patients support the proposal that homocyst(e)ine concentrations are elevated in those who die within the first few years of follow-up. Thus, homocyst(e)ine elevation may be a late-stage predictor of CHD.
The above results suggest that homocyst(e)ine may increase after a
cardiovascular event, possibly in relation to an
inflammatory response. We previously documented that both serum
albumin36 and CRP23 levels were
associated with increased risk of CHD in the MRFIT nested case-control
study, especially among cigarette smokers. Both variables are
acute-phase proteins, and their levels increase (CRP) or decrease
(albumin) with inflammation and after MI. We found a weak but
significant association of CRP with blood homocyst(e)ine values
(Figure). Fibrinogen, also an acute-phase reactant, was correlated with
homocyst(e)ine levels in patients with CHD and control subjects in the
Prospective Cardiovascular Münster (PROCAM)
study. The significant association of homocyst(e)ine levels and CHD
cases as compared to controls was lost when levels of fibrinogen were
added to the multiple logistic analyses.37 It is
not clear, however, whether the analyses were controlled for
smoking. Fibrinogen levels are increased in smokers. The studies
involving CRP23 and albumin36 and an
increased risk of CHD did control for smoking.
Elevation of homocyst(e)ine concentration has also been reported in patients with venous thromboses38 39 and in patients with breast cancer.40 Treatment of patients with breast cancer with the antiestrogen tamoxifen, which reduces the risks of recurrent breast cancer, has been associated with a decrease in homocyst(e)ine levels.40
A fourth possibility is that the prospective studies lack enough cases (ie, power) to identify the risk associated with high homocyst(e)ine concentrations and CHD. However, the consistency of the negative to very low risk associations found in almost all of the longitudinal studies suggests that the number of cases or power does not account for the failure to find an increased risk associated with high homocyst(e)ine levels. The 95% confidence limits for the OR in MRFIT for quartile 1 versus quartile 4 were 0.55 to 1.54.
The problem of power is exacerbated if the association of homocyst(e)ine levels and risk of cardiovascular disease is restricted to individuals who have a primary genetic abnormality in homocyst(e)ine metabolism. However, the association of genetic abnormalities in homocyst(e)ine metabolism and risk of CHD is inconclusive at present.41 42 43 44 45 46 47 We had few individuals with very high homocyst(e)ine levels in this study, but the numbers were similar for the case patients and control subjects.
A fifth possibility concerning interpretation of homocyst(e)ine data is that elevated homocyst(e)ine levels are associated with other risk factors related to CHD (ie, substantial confounding).
The Hordaland study in Norway48 of 7591 men and 8585 women aged 40 to 67 years is the most extensive analysis of the determinants of homocyst(e)ine in conjunction with other cardiovascular risk factors. Homocyst(e)ine concentrations increased with age in men and with the number of cigarettes smoked per day, especially among women. There was a positive association of homocyst(e)ine values with total cholesterol, blood pressure, and heart rate, and an inverse association with physical activity. Several other studies have also documented a correlation between homocyst(e)ine and cardiovascular risk factors, especially elevated blood pressure. In the Tromso study,17 homocyst(e)ine concentrations were significantly associated with total cholesterol, systolic blood pressure, and cigarette smoking, and investigators in the Physicians' Health Study18 observed a high positive correlation of homocyst(e)ine with systolic blood pressure. Investigators in the British Regional Heart Study noted a strong association of homocyst(e)ine levels with blood creatinine levels; this study included stroke patients who had substantially higher blood pressures (systolic blood pressure, 161 mm Hg) than the control subjects (141 mm Hg). Higher blood pressures, especially systolic blood pressure, are associated with atherosclerotic cardiovascular disease, increasing carotid artery wall thickness, carotid artery stenosis, and higher blood creatinine levels, all of which have been correlated with higher homocyst(e)ine levels.49
Inadequate control or measurement of these other cardiovascular risk factors in statistical analyses, especially in case-control studies, could affect the interpretation of differences in homocyst(e)ine values between cases and control subjects. The levels of the risk factors may have been modified by the disease (eg, decrease in blood pressure after an MI) or by treatment of the elevated risk factors (eg, antihypertensive therapy, lipid lowering drugs, or smoking cessation), masking the confounding effects of these risk factors on the association between homocyst(e)ine concentrations and cardiovascular disease.
It is also possible that high homocyst(e)ine levels, secondary to low folic acid intake or blood folic acid or vitamin B6 levels, are an important risk factor for the progression of atherosclerotic disease to clinical disease among individuals who have atherosclerotic disease. Homocyst(e)ine would not be a primary risk factor but may augment the risk of clinical disease, either through promoting thrombosis, inflammation, and disruption of atherosclerotic plaque or by affecting endothelial function among individuals with atherosclerotic disease.
A recent report has noted that there is a direct correlation between population homocyst(e)ine levels and cardiovascular disease mortality among countries.50 The prospective studies with longer follow-up of participants may be measuring the underlying risk factors for atherosclerotic disease (ie, serum cholesterol, blood pressure, and cigarette smoking) but measuring less consistently the more proximate risk factors such as homocyst(e)ine. In contrast, the studies with shorter follow-up times or the case-control studies of patients who already have clinical coronary artery disease, stroke, or very extensive atherosclerosis may show an association between homocyst(e)ine levels and clinical disease.
It is unlikely that further case-control or prospective studies will resolve issues concerning homocyst(e)ine as an independent risk factor for coronary artery disease and whether low folic acid intake and metabolism are causes of elevated homocyst(e)ine concentrations that subsequently increase the risk of cardiovascular disease.
Clinical trials to determine whether folic acid supplementation will lower homocyst(e)ine levels and risk of cardiovascular disease will likely clarify the relationship among homocyst(e)ine, folic acid, and cardiovascular disease. Several groups are proposing secondary prevention trials. The trials (even if successful in reducing CHD) will not prove that homocyst(e)ine is a risk factor. It is possible that increased folic acid intake will lower homocyst(e)ine concentration and reduce CHD but that the homocyst(e)ine/CHD relationship is not causal. Secondary prevention trials will also not prove whether lowering homocyst(e)ine is effective in the primary prevention of CHD. The public health implications of the trial results, however, would be very important in providing another measure and, probably, a very safe method of reducing CHD. It is also worthwhile to consider experimental studies that will determine the effects of folic acid supplementation on homocyst(e)ine levels, blood pressure, clotting, thrombosis, measures of endothelial function, and vascular function.
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Acknowledgments |
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We thank R. Foran, B. Hauth, and M. Mistrik for expert technical assistance. The mortality follow-up, storage of sera, and data analysis for this article were supported by research grant RO1-HL-43232 from the National Institutes of Health, Bethesda, Md.
Received December 18, 1996; accepted March 27, 1997.
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References |
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H. H. Yu, R. Joubran, M. Asmi, T. Law, A. Spencer, M. Jouma, and N. Rifai Agreement among Four Homocysteine Assays and Results in Patients with Coronary Atherosclerosis and Controls Clin. Chem., February 1, 2000; 46(2): 258 - 264. [Abstract] [Full Text] [PDF]
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K. ROBINSON Homocysteine, B vitamins, and risk of cardiovascular disease Heart, February 1, 2000; 83(2): 127 - 130. [Full Text]
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I. F. W. McDowell and D. Lang Homocysteine and Endothelial Dysfunction: A Link with Cardiovascular Disease J. Nutr., February 1, 2000; 130(2): 369 - 369. [Abstract] [Full Text]
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 V. Fonseca, S. C. Guba, and L. M. Fink Hyperhomocysteinemia and the Endocrine System: Implications for Atherosclerosis and Thrombosis Endocr. Rev., October 1, 1999; 20(5): 738 - 759. [Abstract] [Full Text]
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P H Whincup, H Refsum, I J Perry, R Morris, M Walker, L Lennon, A Thomson, P M Ueland, and S B J Ebrahim Serum total homocysteine and coronary heart disease: prospective study in middle aged men Heart, October 1, 1999; 82(4): 448 - 454. [Abstract] [Full Text] [PDF]
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 L. A. Bortolotto, M. E. Safar, E. Billaud, C. Lacroix, R. Asmar, G. M. London, and J. Blacher Plasma Homocysteine, Aortic Stiffness, and Renal Function in Hypertensive Patients Hypertension, October 1, 1999; 34(4): 837 - 842. [Abstract] [Full Text] [PDF]
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J. D. Kark, J. Selhub, B. Adler, J. Gofin, J. H. Abramson, G. Friedman, and I. H. Rosenberg Nonfasting Plasma Total Homocysteine Level and Mortality in Middle-Aged and Elderly Men and Women in Jerusalem Ann Intern Med, September 7, 1999; 131(5): 321 - 330. [Abstract] [Full Text] [PDF]
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A. G. Bostom, I. H. Rosenberg, H. Silbershatz, P. F. Jacques, J. Selhub, R. B. D'Agostino, P. W.F. Wilson, and P. A. Wolf Nonfasting Plasma Total Homocysteine Levels and Stroke Incidence in Elderly Persons: The Framingham Study Ann Intern Med, September 7, 1999; 131(5): 352 - 355. [Abstract] [Full Text] [PDF]
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J. W. Eikelboom, E. Lonn, J. Genest Jr., G. Hankey, and S. Yusuf Homocyst(e)ine and Cardiovascular Disease: A Critical Review of the Epidemiologic Evidence Ann Intern Med, September 7, 1999; 131(5): 363 - 375. [Abstract] [Full Text] [PDF]
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K. J. Harjai Potential New Cardiovascular Risk Factors: Left Ventricular Hypertrophy, Homocysteine, Lipoprotein(a), Triglycerides, Oxidative Stress, and Fibrinogen Ann Intern Med, September 7, 1999; 131(5): 376 - 386. [Abstract] [Full Text] [PDF]
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S. J. Kittner, W. H. Giles, R. F. Macko, J. R. Hebel, M. A. Wozniak, R. J. Wityk, P. D. Stolley, B. J. Stern, M. A. Sloan, R. Sherwin, et al. Homocyst(e)ine and Risk of Cerebral Infarction in a Biracial Population : The Stroke Prevention in Young Women Study Stroke, August 1, 1999; 30(8): 1554 - 1560. [Abstract] [Full Text] [PDF]
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F. Nappo, N. De Rosa, R. Marfella, D. De Lucia, D. Ingrosso, A. F. Perna, B. Farzati, and D. Giugliano Impairment of Endothelial Functions by Acute Hyperhomocysteinemia and Reversal by Antioxidant Vitamins JAMA, June 9, 1999; 281(22): 2113 - 2118. [Abstract] [Full Text] [PDF]
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P. M. Ridker Evaluating Novel Cardiovascular Risk Factors: Can We Better Predict Heart Attacks? Ann Intern Med, June 1, 1999; 130(11): 933 - 937. [Abstract] [Full Text] [PDF]
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 S. N. Doshi, J. Goodfellow, M. J. Lewis, and I. F.W. McDowell Homocysteine and endothelial function Cardiovasc Res, June 1, 1999; 42(3): 578 - 582. [Full Text] [PDF]
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A. G. Bostom, H. Silbershatz, I. H. Rosenberg, J. Selhub, R. B. D'Agostino, P. A. Wolf, P. F. Jacques, and P. W. F. Wilson Nonfasting Plasma Total Homocysteine Levels and All-Cause and Cardiovascular Disease Mortality in Elderly Framingham Men and Women Arch Intern Med, May 24, 1999; 159(10): 1077 - 1080. [Abstract] [Full Text] [PDF]
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P. M. Ridker, J. E. Manson, J. E. Buring, J. Shih, M. Matias, and C. H. Hennekens Homocysteine and Risk of Cardiovascular Disease Among Postmenopausal Women JAMA, May 19, 1999; 281(19): 1817 - 1821. [Abstract] [Full Text] [PDF]
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A. G. Bostom and J. Selhub Homocysteine and Arteriosclerosis : Subclinical and Clinical Disease Associations Circulation, May 11, 1999; 99(18): 2361 - 2363. [Full Text] [PDF]
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S. K. Osganian, M. J. Stampfer, D. Spiegelman, E. Rimm, J. A. Cutler, H. A. Feldman, D. H. Montgomery, L. S. Webber, L. A. Lytle, L. Bausserman, et al. Distribution of and Factors Associated With Serum Homocysteine Levels in Children: Child and Adolescent Trial for Cardiovascular Health JAMA, April 7, 1999; 281(13): 1189 - 1196. [Abstract] [Full Text] [PDF]
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A. G. BOSTOM and B. F. CULLETON Hyperhomocysteinemia in Chronic Renal Disease J. Am. Soc. Nephrol., April 1, 1999; 10(4): 891 - 900. [Full Text]
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M. R. Malinow, A. G. Bostom, and R. M. Krauss Homocyst(e)ine, Diet, and Cardiovascular Diseases : A Statement for Healthcare Professionals From the Nutrition Committee, American Heart Association Circulation, January 12, 1999; 99(1): 178 - 182. [Full Text] [PDF]
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K. Demuth, N. Moatti, O. Hanon, M. O. Benoit, M. Safar, and X. Girerd Opposite Effects of Plasma Homocysteine and the Methylenetetrahydrofolate Reductase C677T Mutation on Carotid Artery Geometry in Asymptomatic Adults Arterioscler. Thromb. Vasc. Biol., December 1, 1998; 18(12): 1838 - 1843. [Abstract] [Full Text] [PDF]
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C. D. A. Stehouwer, M. P. Weijenberg, M. van den Berg, C. Jakobs, E. J. M. Feskens, and D. Kromhout Serum Homocysteine and Risk of Coronary Heart Disease and Cerebrovascular Disease in Elderly Men : A 10-Year Follow-Up Arterioscler. Thromb. Vasc. Biol., December 1, 1998; 18(12): 1895 - 1901. [Abstract] [Full Text] [PDF]
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D. W. Jacobsen Acquired Hyperhomocysteinemia in Heart Transplant Recipients Clin. Chem., November 1, 1998; 44(11): 2238 - 2239. [Full Text] [PDF]
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D. W. Jacobsen Homocysteine and vitamins in cardiovascular disease Clin. Chem., August 1, 1998; 44(8): 1833 - 1843. [Abstract] [Full Text] [PDF]
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L. H. Kuller and R. W. Evans Homocysteine, Vitamins, and Cardiovascular Disease Circulation, July 21, 1998; 98(3): 196 - 199. [Full Text] [PDF]
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A. R. Folsom, F. J. Nieto, P. G. McGovern, M. Y. Tsai, M. R. Malinow, J. H. Eckfeldt, D. L. Hess, and C. E. Davis Prospective Study of Coronary Heart Disease Incidence in Relation to Fasting Total Homocysteine, Related Genetic Polymorphisms, and B Vitamins : The Atherosclerosis Risk in Communities (ARIC) Study Circulation, July 21, 1998; 98(3): 204 - 210. [Abstract] [Full Text] [PDF]
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N. J. Wald, H. C. Watt, M. R. Law, D. G. Weir, J. McPartlin, and J. M. Scott Homocysteine and Ischemic Heart Disease: Results of a Prospective Study With Implications Regarding Prevention Arch Intern Med, April 27, 1998; 158(8): 862 - 867. [Abstract] [Full Text] [PDF]
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G. S. Omenn, S. A. A. Beresford, and A. G. Motulsky Preventing Coronary Heart Disease : B Vitamins and Homocysteine Circulation, February 10, 1998; 97(5): 421 - 424. [Full Text] [PDF]
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 J. C. Chambers, P. M. Ueland, M. Wright, C. J. Dore, H. Refsum, and J. S. Kooner Investigation of Relationship Between Reduced, Oxidized, and Protein-Bound Homocysteine and Vascular Endothelial Function in Healthy Human Subjects Circ. Res., July 20, 2001; 89(2): 187 - 192. [Abstract] [Full Text] [PDF]
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P. M. Ridker, J. Shih, T. J. Cook, M. Clearfield, J. R. Downs, A. D. Pradhan, S. E. Weis, A. M. Gotto Jr, and for the Air Force/Texas Coronary Atherosclerosis P Plasma Homocysteine Concentration, Statin Therapy, and the Risk of First Acute Coronary Events Circulation, April 16, 2002; 105(15): 1776 - 1779. [Abstract] [Full Text] [PDF]
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